tbuckley/cabot-search huggingface dataset:
Transformer-based biomarker prediction from colorectal cancer histology: A large-scale multicentric study
Authors: Sophia J. Wagner, Daniel Reisenbüchler, Nicholas P. West, Jan Moritz Niehues, Jiefu Zhu, Sebastian Foersch, Gregory Patrick Veldhuizen, Philip Quirke, Heike I. Grabsch, Piet A. van den Brandt, Gordon G.A. Hutchins, Susan D. Richman, Tanwei Yuan, Rupert Langer, Josien C.A. Jenniskens, Kelly Offermans, Wolfram Mueller, Richard Gray, Stephen B. Gruber, Joel K. Greenson, Gad Rennert, Joseph D. Bonner, Daniel Schmolze, Jitendra Jonnagaddala, Nicholas J. Hawkins, Robyn L. Ward, Dion Morton, Matthew Seymour, Laura Magill, Marta Nowak, Jennifer Hay, Viktor H. Koelzer, David N. Church, Christian Matek, Carol Geppert, Chaolong Peng, Cheng Zhi, Xiaoming Ouyang, Jacqueline A. James, Maurice B. Loughrey, Manuel Salto-Tellez, Hermann Brenner, Michael Hoffmeister, Daniel Truhn, Julia A. Schnabel, Melanie Boxberg, Tingying Peng, Jakob Nikolas Kather, David Church, Enric Domingo, Joanne Edwards, Bengt Glimelius, Ismail Gogenur, Andrea Harkin, Jen Hay, Timothy Iveson, Emma Jaeger, Caroline Kelly, Rachel Kerr, Noori Maka, Hannah Morgan, Karin Oien, Clare Orange, Claire Palles, Campbell Roxburgh, Owen Sansom, Mark Saunders, Ian Tomlinson
Journal: Cancer Cell (2023)

Deep learning (DL) can accelerate the prediction of prognostic biomarkers from routine pathology slides in colorectal cancer (CRC). However, current approaches rely on convolutional neural networks (CNNs) and have mostly been validated on small patient cohorts. Here, we develop a new transformer-based pipeline for end-to-end biomarker prediction from pathology slides by combining a pre-trained transformer encoder with a transformer network for patch aggregation. Our transformer-based approach substantially improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms. After training and evaluating on a large multicenter cohort of over 13,000 patients from 16 colorectal cancer cohorts, we achieve a sensitivity of 0.99 with a negative predictive value of over 0.99 for prediction of microsatellite instability (MSI) on surgical resection specimens. We demonstrate that resection specimen-only training reaches clinical-grade performance on endoscopic biopsy tissue, solving a long-standing diagnostic problem.
Pathogen-driven CRISPR screens identify TREX1 as a regulator of DNA self-sensing during influenza virus infection
Authors: Cason R. King, Yiping Liu, Katherine A. Amato, Grace A. Schaack, Clayton Mickelson, Autumn E. Sanders, Tony Hu, Srishti Gupta, Ryan A. Langlois, Judith A. Smith, Andrew Mehle
Journal: Cell Host & Microbe (2023)
Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer’s disease via MFG-E8
Authors: Makis Tzioras, Michael J.D. Daniels, Caitlin Davies, Paul Baxter, Declan King, Sean McKay, Balazs Varga, Karla Popovic, Madison Hernandez, Anna J. Stevenson, Jack Barrington, Elizabeth Drinkwater, Julia Borella, Rebecca K. Holloway, Jane Tulloch, Jonathan Moss, Clare Latta, Jothy Kandasamy, Drahoslav Sokol, Colin Smith, Veronique E. Miron, Ragnhildur Thóra Káradóttir, Giles E. Hardingham, Christopher M. Henstridge, Paul M. Brennan, Barry W. McColl, Tara L. Spires-Jones
Journal: Cell Reports Medicine (2023)

Synapse loss correlates with cognitive decline in Alzheimer's disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence for any glial involvement in synapse removal in human AD remains to be established. Here we observe astrocytes and microglia from human brains contain greater amounts of synaptic protein in AD compared with non-disease controls, and that proximity to amyloid-β plaques and the APOE4 risk gene exacerbate this effect. In culture, mouse and human astrocytes and primary mouse and human microglia phagocytose AD patient-derived synapses more than synapses from controls. Inhibiting interactions of MFG-E8 rescues the elevated engulfment of AD synapses by astrocytes and microglia without affecting control synapse uptake. Thus, AD promotes increased synapse ingestion by human glial cells at least in part via an MFG-E8 opsonophagocytic mechanism with potential for targeted therapeutic manipulation.
Population serum proteomics uncovers a prognostic protein classifier for metabolic syndrome
Authors: Xue Cai, Zhangzhi Xue, Fang-Fang Zeng, Jun Tang, Liang Yue, Bo Wang, Weigang Ge, Yuting Xie, Zelei Miao, Wanglong Gou, Yuanqing Fu, Sainan Li, Jinlong Gao, Menglei Shuai, Ke Zhang, Fengzhe Xu, Yunyi Tian, Nan Xiang, Yan Zhou, Peng-Fei Shan, Yi Zhu, Yu-ming Chen, Ju-Sheng Zheng, Tiannan Guo
Journal: Cell Reports Medicine (2023)

Metabolic syndrome (MetS) is a complex metabolic disorder with a global prevalence of 20%–25%. Early identification and intervention would help minimize the global burden on healthcare systems. Here, we measured over 400 proteins from ∼20,000 proteomes using data-independent acquisition mass spectrometry for 7,890 serum samples from a longitudinal cohort of 3,840 participants with two follow-up time points over 10 years. We then built a machine-learning model for predicting the risk of developing MetS within 10 years. Our model, composed of 11 proteins and the age of the individuals, achieved an area under the curve of 0.774 in the validation cohort (n = 242). Using linear mixed models, we found that apolipoproteins, immune-related proteins, and coagulation-related proteins best correlated with MetS development. This population-scale proteomics study broadens our understanding of MetS and may guide the development of prevention and targeted therapies for MetS.
Tumor-associated monocytes promote mesenchymal transformation through EGFR signaling in glioma
Authors: Yiyun Chen, Ran Huo, Weirong Kang, Yuwei Liu, Zheng Zhao, Weilun Fu, Ruochen Ma, Xiaomeng Zhang, Jihong Tang, Zhihan Zhu, Qingyang Lyu, Yi Huang, Mengli Yan, Biaobin Jiang, Ruichao Chai, Zhaoshi Bao, Zheng Hu, Weiping Wang, Tao Jiang, Yong Cao, Jiguang Wang
Journal: Cell Reports Medicine (2023)

The role of brain immune compartments in glioma evolution remains elusive. We profile immune cells in glioma microenvironment and the matched peripheral blood from 11 patients. Glioblastoma exhibits specific infiltration of blood-originated monocytes expressing epidermal growth factor receptor (EGFR) ligands EREG and AREG, coined as tumor-associated monocytes (TAMo). TAMo infiltration is mutually exclusive with EGFR alterations (p = 0.019), while co-occurring with mesenchymal subtype (p = 4.7 × 10−7) and marking worse prognosis (p = 0.004 and 0.032 in two cohorts). Evolutionary analysis of initial-recurrent glioma pairs and single-cell study of a multi-centric glioblastoma reveal association between elevated TAMo and glioma mesenchymal transformation. Further analyses identify FOSL2 as a TAMo master regulator and demonstrates that FOSL2-EREG/AREG-EGFR signaling axis promotes glioma invasion in vitro. Collectively, we identify TAMo in tumor microenvironment and reveal its driving role in activating EGFR signaling to shape glioma evolution.
Aortic size distribution among normal, hypertension, bicuspid, and Marfan populations
Authors: Jinlin Wu, Weiyue Zeng, Xiaoshan Li, Jiade Zhu, Chenyu Zhou, Ruixin Fan, Tucheng Sun, Hongwen Fei, Xin Li
Journal:  (2023)

Abstract Aims Large-scale investigations on ascending aortic diameter, especially in the Asian population, are lacking. Furthermore, relevant evidence regarding the distribution of hypertension (HP), bicuspid aortic valve (BAV), and Marfan syndrome (MFS) is scarce. We aimed to examine the distribution of ascending aortic diameter in these populations in China. Methods and results The data of a total number of 698 795 individuals who underwent cardiac ultrasound were subjected to retrospective analysis. After screening, 647 087 individuals were included in the final analysis. In the normal population, the mean ascending aortic diameter was 28.1 ± 3.2 mm (27.2 ± 3.1 mm in women vs. 29.0 ± 3.1 mm in men) (P &amp;lt; 0.001). Aortic diameter increased gradually with age (P &amp;lt; 0.001). The prevalence of aortic dilation, aneurysm, and dissection in individuals with HP was 12.83%, 2.70%, and 4.77%, respectively. In individuals with MFS, the corresponding rates were 43.92%, 35.31%, and 26.11%. Notably, although BAV patients had high incidences of aortic dilation (37.00%) and aortic aneurysm (16.46%), the incidence of aortic dissection was relatively low (0.74%). Most cases of aortic dissection occurred at an aortic diameter of less than 55 mm. However, in the overall population, the incidence of aortic dissection significantly increased with the increase in the aortic diameter, revealing the existence of an ‘aortic paradox’. Conclusions (i) The ascending diameter increases with age and is larger in men than in women; (ii) ‘Aortic paradox’ is explained; (iii) BAV bears a high rate of aortic dilation, but a low incidence of aortic dissection.
Validity of Meta-Analytical Data on Cutaneous Adverse Events with Phosphoinositide 3-Kinase Inhibitors—Reply
Authors: Abdulhadi Jfri, Lauren Guggina
Journal: JAMA Oncology (2023)

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Validity of Meta-Analytical Data on Cutaneous Adverse Events With Phosphoinositide 3-Kinase Inhibitors
Authors: Dan-Na Wu, Guo Yu, Guo-Fu Li
Journal: JAMA Oncology (2023)

To the Editor We read with great interest the recent meta-analysis by Jfri and colleagues1 assessing the association of rash with phosphoinositide 3-kinase (PI3K) inhibitors and caution the validity of their meta-analytical data.
<i>De Novo</i> Mutation Rates in Sticklebacks
Authors: Chaowei Zhang, Kerry Reid, Arthur F Sands, Antoine Fraimout, Mikkel Heide Schierup, Juha Merilä
Journal: Molecular Biology and Evolution (2023)

Mutation rate is a fundamental parameter in population genetics. Apart from being an important scaling parameter for demographic and phylogenetic inference, it allows one to understand at what rate new genetic diversity is generated and what the expected level of genetic diversity is in a population at equilibrium. However, except for well-established model organisms, accurate estimates of de novo mutation rates are available for a very limited number of organisms from the wild. We estimated mutation rates (µ) in two marine populations of the nine-spined stickleback (Pungitius pungitius) with the aid of several 2- and 3-generational family pedigrees, deep (>50×) whole-genome resequences and a high-quality reference genome. After stringent filtering, we discovered 308 germline mutations in 106 offspring translating to µ = 4.83 × 10-9 and µ = 4.29 × 10-9 per base per generation in the two populations, respectively. Up to 20% of the mutations were shared by full-sibs showing that the level of parental mosaicism was relatively high. Since the estimated µ was 3.1 times smaller than the commonly used substitution rate, recalibration with µ led to substantial increase in estimated divergence times between different stickleback species. Our estimates of the de novo mutation rate should provide a useful resource for research focused on fish population genetics and that of sticklebacks in particular.
Cost-Effectiveness of Pharmacotherapy for the Treatment of Obesity in Adolescents
Authors: Francesca Lim, Brandon K. Bellows, Sarah Xinhui Tan, Zainab Aziz, Jennifer A. Woo Baidal, Aaron S. Kelly, Chin Hur
Journal: JAMA Network Open (2023)

Importance Antiobesity pharmacotherapy is recommended for adolescents ages 12 years and older with obesity. Several medications have been approved by the US Food and Drug Administration for adolescent use, but the most cost-effective medication remains unclear. Objective To estimate the cost-effectiveness of lifestyle counseling alone and as adjunct to liraglutide, mid-dose phentermine and topiramate (7.5 mg phentermine and 46 mg topiramate), top-dose phentermine and topiramate (15 mg phentermine and 92 mg topiramate), or semaglutide among adolescent patients with obesity. Design, Setting, and Participants This economic evaluation used a microsimulation model to project health and cost outcomes of lifestyle counseling alone and adjunct to liraglutide, mid-dose phentermine and topiramate, top-dose phentermine and topiramate, or semaglutide over 13 months, 2 years, and 5 years among a hypothetical cohort of 100 000 adolescents with obesity, defined as an initial body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 37. Model inputs were derived from clinical trials, published literature, and national sources. Data were analyzed from April 2022 to July 2023. Exposures Lifestyle counseling alone and as adjunct to liraglutide, mid-dose phentermine and topiramate, top-dose phentermine and topiramate, or semaglutide. Main Outcomes and Measures The main outcome was quality-adjusted life years (QALYs), costs (2022 US dollars), and incremental cost-effectiveness ratios (ICERs), with future costs and QALYs discounted 3.0% annually. A strategy was considered cost-effective if the ICER was less than $100 000 per QALY gained. The preferred strategy was determined as the strategy with the greatest increase in QALYs while being cost-effective. One-way and probabilistic sensitivity analyses were used to assess parameter uncertainty. Results The model simulated 100 000 adolescents at age 15 with an initial BMI of 37, of whom 58 000 (58%) were female. At 13 months and 2 years, lifestyle counseling was estimated to be the preferred strategy. At 5 years, top-dose phentermine and topiramate was projected to be the preferred strategy with an ICER of $56 876 per QALY gained vs lifestyle counseling. Semaglutide was projected to yield the most QALYs, but with an unfavorable ICER of $1.1 million per QALY gained compared with top-dose phentermine and topiramate. Model results were most sensitive to utility of weight reduction and weight loss of lifestyle counseling and top-dose phentermine and topiramate. Conclusions and Relevance In this economic evaluation of pharmacotherapy for adolescents with obesity, top-dose phentermine and topiramate as adjunct to lifestyle counseling was estimated to be cost-effective after 5 years. Long-term clinical trials in adolescents are needed to fully evaluate the outcomes of pharmacotherapy, especially into adulthood.
TNF‐like weak inducer of apoptosis inhibition is comparable to IL‐13 blockade in ameliorating atopic dermatitis inflammation
Authors: Rinkesh K. Gupta, Jacqueline Miller, Michael Croft
Journal: Allergy (2023)

Abstract Background Targeting IL‐13 is highly efficacious in patients with Th2‐biased atopic dermatitis (AD), but inhibition of other inflammatory molecules might also limit disease. We investigated the importance of the TNF family cytokine TNF‐like weak inducer of apoptosis (TWEAK; TNFSF12) to keratinocyte dysregulation and the pathogenesis of AD in mice and also tested if blocking TWEAK has a similar therapeutic effect as targeting IL‐13. Methods Conditional knockout mice lacking Fn14 (TNFRSF12A), the receptor for TWEAK, only in keratinocytes, were repetitively sensitized with house dust mite allergen and analyzed for AD‐like skin inflammation. To determine the translational potential, wild‐type mice with AD were therapeutically treated with anti‐TWEAK and/or anti‐IL‐13 antibodies, and skin inflammation was assessed. Results Mice deficient in Fn14 in keratinocytes were resistant to developing maximal clinical features of AD, exhibiting reduced epidermal hyperplasia and dermal thickening, less skin infiltration of immune cells, and downregulated inflammatory gene expression. Moreover, therapeutic neutralization of TWEAK in wild‐type mice with AD reduced all of the pathological features to a comparable extent as blocking IL‐13. Conclusions The activity of TWEAK in keratinocytes contributes to AD development, and neutralizing TWEAK represents a future potential therapeutic option in human AD similar to targeting IL‐13.
Reversed urban–rural gradient in COVID-19 seroprevalence and related factors in a nationally representative survey, Poland, 29 March to 14 May 2021
Authors: Michał Czerwiński, Małgorzata Stępień, Grzegorz Juszczyk, Małgorzata Sadkowska-Todys, Adam Zieliński, Jakub Rutkowski, Magdalena Rosińska
Journal: Eurosurveillance (2023)

BackgroundWe anticipated that people in rural areas and small towns with lower population density, lower connectivity and jobs less dependent on social interaction will be less exposed to COVID-19. Still, other variables correlated with socioeconomic inequalities may have a greater impact on transmission.AimWe investigated how COVID-19 affected rural and urban communities in Poland, focussing on the most exposed groups and disparities in SARS-CoV-2 transmission.MethodsA random digit dial sample of Polish adults stratified by region and age was drawn from 29 March to 14 May 2021. Serum samples were tested for anti-S1 and anti-N IgG antibodies, and positive results in both assays were considered indicative of past infection. Seroprevalence estimates were weighted to account for non-response. Adjusted odds ratios (AORs) were calculated using multivariable logistic regression.ResultsThere was serological evidence of infection in 32.2% (95% CI: 30.2-34.4) of adults in rural areas/small towns (< 50,000 population) and 26.6% (95% CI: 24.9-28.3) in larger cities. Regional SARS-CoV-2 seroprevalence ranged from 23.4% (95% CI: 18.3-29.5) to 41.0% (95% CI: 33.5-49.0) and was moderately positively correlated (R = 0.588; p = 0.017; n = 16) with the proportion of respondents living in rural areas or small cities. Upon multivariable adjustment, both men (AOR = 1.60; 95% CI: 1.09-2.35) and women (AOR = 2.26; 95% CI: 1.58-3.21) from these areas were more likely to be seropositive than residents of larger cities.ConclusionsWe found an inverse urban-rural gradient of SARS-CoV-2 infections during early stages of the COVID-19 pandemic in Poland and suggest that vulnerabilities of populations living in rural areas need to be addressed.
Temporal relationships between <i>Staphylococcus aureus</i> colonization, <i>filaggrin</i> expression, and pediatric atopic dermatitis
Authors: Arya Dahal, Wan Chi Chang, Cassandra Almasri, Elisabet Johansson, Makenna Hurd, Veronica Velasquez, Brittany Grashel, Daniel Spagna, Seth Jenkins, David Morgan, Latha Satish, Lisa J. Martin, Jocelyn M. Biagini, Gurjit K. Khurana Hershey
Journal: Allergy (2023)

Abstract Background Atopic dermatitis (AD) is characterized by Staphylococcus aureus ( S. aureus ) colonization. Longitudinal early life data delineating relationships of S. aureus colonization, barrier function, and AD outcomes are lacking. We define longitudinal S. aureus endotypes and AD pathogenesis in early life. Methods We defined longitudinal S. aureus skin colonization phenotypes across two annual visits (non‐colonized: V1 − V2 − , early transient: V1 + V2 − , late‐onset: V1 − V2 + , persistent: V1 + V2 + ) in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort. We analyzed AD severity, sensitization, and skin barrier function across phenotypes, and performed mediation analyses between colonization and FLG expression. Results Persistent S. aureus colonization was associated with increased SCORAD at V1 (33.5 vs. 19.0, p = .004) and V2 (40.1 vs.16.9, p &lt; .001), and lower non‐lesional (NL) FLG at V2 (1.77 vs. 4.09, p = .029) compared to the non‐colonized phenotype, with early transient and late‐onset colonization as intermediate phenotypes. Children colonized at V2 demonstrated a decrease in NL‐ FLG expression from V1 to V2 compared to those non‐colonized at V2 ( p = .0012), who maintained expression. This effect remained significant even after adjusting for V1 colonization and SCORAD ( p = .011). Conclusions Our findings are the first to present longitudinal quantitative FLG expression and S. aureus skin colonization in early life and suggest that a decrease in NL‐ FLG drives later colonization. Hence, therapies to maintain NL‐ FLG expression may prevent S. aureus colonization. Further, a longitudinal AD endotype of persistent colonization is characterized by increased AD severity, sensitization, and decreasing NL‐ FLG .
Interpreting Cost-Effectiveness Analyses of Anti-Obesity Medications for the Treatment of Adolescent Obesity—Reading the Tea Leaves
Authors: Davene R. Wright, Andrea Luviano, Joseph A. Skelton
Journal: JAMA Network Open (2023)

Francesca Lim, MS; Brandon K. Bellows, PharmD, MS; Sarah Xinhui Tan, BS; Zainab Aziz, BS; Jennifer A. Woo Baidal, MD, MPH; Aaron S. Kelly, PhD; Chin Hur, MD, MPH
Stage-Specific Risk of Recurrence and Death From Melanoma in Denmark, 2008-2021
Authors: Neel M. Helvind, Marie Brinch-Møller Weitemeyer, Annette H. Chakera, Helle W. Hendel, Eva Ellebæk, Inge Marie Svane, Mette W. Kjærskov, Sophie Bojesen, Helle Skyum, Søren K. Petersen, Lars Bastholt, Christoffer Johansen, Pernille E. Bidstrup, Lisbet R. Hölmich
Journal: JAMA Dermatology (2023)

To ensure optimal treatment and surveillance of patients with melanoma, knowledge of the clinical stage-specific risk of recurrence, mortality, and recurrence patterns across the American Joint Committee on Cancer Eighth Edition (AJCC8) substages is needed.